THE P75 NEUROTROPHIN RECEPTOR MEDIATES NEURONAL APOPTOSIS AND IS ESSENTIAL FOR NATURALLY-OCCURRING SYMPATHETIC NEURON DEATH

To determine whether the p75 neurotrophin receptor (p75NTR) plays a ro le in naturally occurring neuronal death, we examined neonatal sympath etic neurons that express both the TrkA tyrosine kinase receptor and p 75NTR. When sympathetic neuron survival is maintained with low quantit ies of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Func tion-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological rel evance of these culture findings, we examined sympathetic neurons in B DNF-/- and p75NTR-/- mice. In BDNF-/- mice, sympathetic neuron number is increased relative to BDNF+/+ littermates, and in p75NTR-/- mice, t he normal period of sympathetic neuron death does not occur, with neur onal attrition occurring later in life. This deficit in apoptosis is i ntrinsic to sympathetic neurons, since cultured p75NTR-/- neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this m echanism is essential for naturally occurring sympathetic neuron death .